The nervous system routinely sends coded signals that result in sensation. Certain types of lesions to either the central or peripheral nervous system can result in an alteration of sensation resulting in pain. Research into persistent or chronic pain has focused mainly on the spinal cord and brain, with little being done to examine the peripheral nervous system. This is so even though researchers and physicians who treat persistent pain syndromes know that the peripheral nervous system is the origin of much of the pain needing treatment.
Even though the peripheral nervous system is identified as the origin of most persistent pain, such pain usually has no known cause. The lack of knowledge concerning the cause of persistent pain hinders research and development of therapeutics to treat such pain. Many researchers refer to the puzzle of pain when referring to persistent neurogenic pain. The cause of neurogenic pain is only well-defined when there has been a history of direct trauma to the nerve. Most persistent pain, however, develops slowly near an area of soft tissue injury. The basis of the present invention is that persistent pain can develop as a response to often clinically, non-detectable tissue injury, not only as a response to direct trauma. After an injury, there appears to be a functional disturbance of the nerve, leading to demonstration of pain behavior.
Neuropathic pain is defined here as pain attributed to a functional disturbance of a nerve, which can occur as a result of alterations and/or injury to nerves. It can occur by a variety of mechanisms including irritation, injury and compression of the peripheral nerves. The symptoms of neuropathic pain usually include a burning sensation, tingling, or electric-shock-like feelings that may be triggered by even a very light touch. Human persistent pain conditions are organized into two categories: Complex Regional Pain Syndrome I (CRPS I) and Complex Regional Pain Syndrome II (CRPS II). CRPS I refers to pain without obvious nerve injury while CRPS II refers to pain with known nerve injury (Merskey, H. and N. Bogduk. 1994. Classification of Chronic Pain, Second Edition, IASP Press). All current animal models involve some type of known nerve injury. Yet, over 90% of persistent pain treated by physicians has no known nerve injury as a cause, although the cause is attributed to being neurogenic in origin. There is a long-standing need for a standard animal model for non-traumatic neurogenic pain, a category into which most patients with persistent neuropathic pain fall.
Any physical change to a nerve can cause physiologic alterations depending on the nerve's receptor organ and the direction of its electric current. Pressure on a nerve is capable of causing nondestructive (non-traumatic) injury to the nerve that can be seen as changes in things such as blood flow of the vasonavorum, accumulation of edema within the nerve, alteration in axonal flow, and a change in the electrical conduction of the nerve. Such changes in pressure on a nerve can result in clinical signs and symptoms of nondestructive nerve injury such as behavioral changes of pain with increased sensitivity to light touch, licking of feet, edema, and increased sensitivity to heat and cold. Other physical examination signs commonly seen that are associated with more traumatic and/or destructive nerve injury would include sensory numbness and/or hyperalgesia to heat or cold, limping, chewing of feet, tremors, spasms, clinical weakness, and/or paralysis. The functional change in a nerve depends on the area and force of pressure applied and the resultant changes in blood flow, lymph circulation, and electrical conductance secondary to the pressure. The consequent alterations in a nerve and their subsequent sensory and behavioral changes may not be immediate, as is seen in a quick high-pressure crush-type injury. In fact, there may be delay of a few days to several weeks before an onset of neuropathic pain after a tissue injury, resulting in a compression of a nerve. Therefore, animal models of nerve pain must consider the physiological changes in tissue during healing that result in a clinical picture of delayed onset persistent neuropathic pain. As a result, models that apply direct trauma or irritants to a nerve are not representative of most human persistent pain. Currently available animal models of neuropathic pain result in acute pain and do not mimic the normal tissue repair physiology which occurs after human injuries. Tissue changes can occur after an injury that lead to altered functioning of a nerve and to ultimate development of pain-related behaviors. No animal model is available that explains the gradual development of pain after an injury.
Current animal models have focused on production of pain through strategies such as irritating, cutting, crushing, ligating, or freezing the nerves in order to model a human peripheral nerve injury. Only rarely would such injuries happen in humans. Examples of such animal models include: use of chemical irritants injected into a limb or paw (Liu-Chen, L. Y. et al. 1991. Eur. J. Pharmacol. 15:195–202); transient nerve crush by compressing the nerve with a micro-cuff (Attal, N. et al. 1994. Pain 59:301–312); freezing the sciatic nerve using the technique of sciatic cryoneurolysis (Willenbring, S. et al. 1994. Pain 58:135–140; Wagner, R. et al. 1995. Physiol. Behav. 58:37–41); sciatic nerve partial injury induced by dissecting the nerve into two pieces and only ligating one part (Seltzer, Z. et al. 1990. Pain 43:205–218); sciatic nerve partial cut where only a part of the nerve is transected (Dougherty, P. M. et al. 1992. Brain Res. 20:109–115); sciatic nerve full cut where the nerve is completely transected (Kingery, W. S. et al. 1999. Pain 80:555–566); nerve root ligatures where the lumbar nerve roots are ligated (Kim, S. H. and J. M. Chung. 1992. Pain 50:355–363; Choi, Y. et al. 1994. Pain 59:369–376); polyethylene cuffs to produce a compression injury (Mosconi, T. and L. Kruger. 1996. Pain 64:37–57); use of hemostatic oxidized cellulose that on one side was saturated with an inflammatory stimulus, carrageenan, or complete Freund's adjuvant (Eliav, E. et al. 1999. Pain 83:169–182); bee venom injected into rat paw (Chen, H. S. et al. 2000. Neurosci. Lett. 284:45–48); scalding of rat paw (Lofgren, O. et al. 1997. Acta Physiol. Scand. 161:289–294); photochemically-induced laser lesion of sciatic nerve (Gazelius, B. et al. 1996. Neuroreport. 4:2619–2623); use of zymosan on the sciatic nerve (Chacur, M. et al. 2000. American Pain Society Poster Presentation); and most recently, spared nerve injury where two or three terminal branches of the sciatic nerve are transected (Decosterd, I. and C. J. Woolf. 2000. Pain 87:149–158). All of these animal models rely on production of a destructive nerve injury through direct nerve trauma, irritation, or an immune response. The most popular of these current models for chronic pain is known as the Chronic Constriction Injury (CCI) model where a sciatic nerve injury is induced by tying four chromic gut sutures loosely around the nerve (Bennett, G. J and Y. K. Xie. 1998. Pain 33:87–107). However, this model produces animals that have difficulty walking due to the immediate, acute pain and swelling seen in the leg where the procedure is performed. As a result, special attention to animal care is needed for these animals for 3 to 4 days. None of the current models provide animals that are fully ambulatory within minutes of the procedure and require no special care.
The need for a standard animal model for pain without clinical evidence of nerve injury has been recognized and recently preliminary attempts have been made. Reyna et al. (1999. ICLAS, Palma de Malloren '99, May 26–28; 1999) developed an open surgical rat model for CRPS I that involved surgical placement by the tibial nerve of Type II collagen (American Pain Society Annual Meeting, November, 2000). This surgical model produced pain responses in the animals characteristic of human persistent neuropathic pain. The responses were delayed in onset by about 14 days. The responses included sensitivity to light touch (mechanical allodynia), and persisted for up to 43 days. In addition, these animals exhibited an analgesic response to morphine sulfate and gabapentin.
Additional models for persistent neuropathic pain are needed, in particular models that require minimal tissue injury.